Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin.

Abstract

The potassium ionophore nigericin induces cell death and promotes the maturation and release of IL-1beta in lipopolysaccharide (LPS)-primed monocytes and macrophages, the latter depending on caspase-1 activation by an unknown mechanism. Here, we investigate the pathway that triggers cell death and activates caspase-1. We show that without LPS priming, nigericin alone triggered caspase-1 activation and IL-18 generation in THP-1 monocytic cells. Simultaneously, nigericin induced caspase-1-independent necrotic cell death, which was blocked by the cathepsin B inhibitor CA-074-Me and other cathepsin inhibitors. Cathepsin B activation after nigericin treatment was determined biochemically and corroborated by rapid lysosomal leakage and translocation of cathepsin B to the cytoplasm. IL-18 maturation was prevented by both caspase-1 and cathepsin B inhibitors in THP-1 cells, primary mouse macrophages and human blood monocytes. Moreover, IL-18 generation was reduced in THP-1 cells stably transformed either with cystatin A (an endogenous cathepsin inhibitor) or antisense cathepsin B cDNA. Collectively, our study establishes a critical role for cathepsin B in nigericin-induced caspase-1-dependent IL-18 maturation and caspase-1-independent necrosis.

• Authors: H Hentze, X Y Lin, M S K Choi, A G Porter
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 10 Issue 9 Pg. 956-68 (Sep 2003) ISSN: 1350-9047 [Print] England
• PMID: 12934070 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• CA 074 methyl ester
• Cysteine Proteinase Inhibitors
• Dipeptides
• Interleukin-18
• Lipopolysaccharides
• Calpain
• Cathepsin B
• Caspase 1
• Nigericin

Topics

• Animals
• Bacterial Toxins (antagonists & inhibitors, pharmacology)
• Calpain (metabolism)
• Caspase 1 (metabolism)
• Cathepsin B (antagonists & inhibitors, physiology)
• Cell Line
• Cells, Cultured
• Cysteine Proteinase Inhibitors (pharmacology)
• Dipeptides (pharmacology)
• Interleukin-18 (biosynthesis, metabolism)
• Lipopolysaccharides (pharmacology)
• Macrophages (drug effects, immunology)
• Mice
• Monocytes (cytology, drug effects, enzymology, immunology)
• Necrosis
• Nigericin (antagonists & inhibitors, pharmacology)
• Protein Transport (drug effects)